Biomedical subjects

Michael A Walker

Publications and source records attributed to Michael A Walker.

10 recordsLinked to original sources

PubMed2006

Exploration of the diketoacid integrase inhibitor chemotype leading to the discovery of the anilide-ketoacids chemotype.

Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. A previous study of the diketoacid-based chemotype suggested that there are two aryl-binding domains on integrase. In this study, modifications to the indole-based diketoacid chemotype are explored. It is demonstrated that the indole group can be replaced with secondary but not tertiary (e.g., N-methyl) aniline-based amides without sacrificing in vitro inhibitory activity. The difference in activity between the secondary and tertiary amides is most likely due to the opposite conformational preferences of the amide bonds, s-trans for the secondary-amide and s-cis for the tertiary-amide. However, it was found that the conformational preference of the tertiary amide can be reversed by incorporating the amide nitrogen atom into an indoline heterocycle, resulting in very potent integrase inhibitors.

Amides↗

PubMed2006

Triketoacid inhibitors of HIV-integrase: a new chemotype useful for probing the integrase pharmacophore.

Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. This study reports on the discovery of a new triketoacid-based chemotype that selectively inhibits the strand transfer reaction of HIV-integrase. SAR studies showed that the template binds to integrase in a manner similar to the diketoacid-based inhibitors. Moreover, comparison of the new chemotype to two different diketoacid templates led us to propose two aryl-binding domains in the inhibitor binding site. This information was used to design a new diketoacid template with improved activity against the enzyme.

HIV Integrase↗

PubMed2006

Evaluation of the association between spondylosis deformans and clinical signs of intervertebral disk disease in dogs: 172 cases (1999-2000).

OBJECTIVE: To evaluate the association between spondylosis deformans and clinical signs of intervertebral disk disease (IVDD) in dogs. DESIGN: Retrospective case series. ANIMALS: 210 dogs. PROCEDURE: Records of 172 dogs with clinical signs of IVDD and 38 dogs with other neurologic disorders were reviewed. Signalment, sites of spondylosis, severity of associated osteophytosis, type of disk herniation, and duration of signs were recorded. RESULTS: Dogs with IVDD had significantly fewer sites of involvement and lower grades of spondylosis deformans, compared with those in the non-IVDD group. When groups were adjusted for age and weight via multivariate linear regression, there were no differences in severity of osteophytosis or number of affected sites. Dogs with type II disk disease had higher numbers of affected sites and more severe changes, compared with dogs with type I disk herniation. There was no difference between groups in the rate at which IVDD was diagnosed at sites of spondylosis, compared with the rate at which IVDD was diagnosed in unaffected disk spaces. Areas of spondylosis were closer to sites of IVDD that elicited clinical signs than to randomly chosen intervertebral spaces, and distances between sites of spondylosis and sites of IVDD had a bimodal appearance. CONCLUSIONS AND CLINICAL RELEVANCE: An association may exist between radiographically apparent spondylosis and type II disk disease; type I disk disease was not associated with spondylosis. Spondylosis in radiographs of dogs with suspected type I disk disease is not clinically important. Spatial associations among sites of spondylosis and sites of IVDD may be coincidental or associated with vertebral column biomechanics.

Animals↗

PubMed2005

Developments in antiviral drug design, discovery and development in 2004.

This article summarizes key aspects of progress made during 2004 toward the design, discovery and development of antiviral agents for clinical use. Important developments in the identification, characterization and clinical utility of inhibitors of human immunodeficiency virus; the hepatitis viruses, hepatitis B, hepatitis C; the herpes family of viruses, herpes simplex viruses 1 and 2, varicella zoster virus, Epstein-Barr virus and human cytomegalovirus; the respiratory viruses, influenza, respiratory syncytial virus, human metapneumovirus, picornaviruses, measles and the severe acute respiratory syndrome coronavirus; human papilloma virus; rotavirus; Ebola virus and West Nile virus, are reviewed.

Amino Acid Sequence↗

PubMed2004

Monoclonal antibody mediated intracellular targeting of tallysomycin S(10b).

The potency of tallysomycin S(10b) (TLM S(10b)) an analogue bleomycin was enhanced by up to 875-fold when it was conjugated to the internalizing antibody BR96. Attachment to the antibody is achieved via a Cathepsin B cleavable linker. The enhancement in potency is believed to be a result of cellular uptake of the conjugate upon antigen binding followed by rapid release of the drug inside the lysosome. This method provides a novel approach for increasing the potency and therapeutic index of nominally moderately-active cytotoxic agents.

Antibodies, Monoclonal↗

PubMed2003

Spiral colon bypass in a geriatric Vietnamese potbellied pig.

An 8-year-old potbellied pig was evaluated for anorexia, decreased fecal production, signs of depression, inappetence, and abdominal distension. During hospitalization, a tooth root impaction and abscess were diagnosed, and abdominal radiography revealed severely distended, gas-filled large and small intestines. Exploratory laparotomy revealed a stricture of the proximal centripetal loop of the spiral colon and megacolon of the proximal portion of the spiral colon and cecum. A side-to-side spiral colon anastomosis was performed to create a partial bypass of the spiral colon. The success of this procedure suggests that spiral colon bypass is a treatment option for spiral colon stricture formation in potbellied pigs. Spiral colon stricture formation should be considered as a differential diagnosis in geriatric potbellied pigs that are anorectic, have abdominal distension, and have decreased fecal production.

Anastomosis, Surgical↗

PubMed2002

Doxorubicin immunoconjugates containing bivalent, lysosomally-cleavable dipeptide linkages.

Bivalent doxorubicin (DOX)-dipeptides (16a-c) were prepared and conjugated to the monoclonal antibody BR96. The dipeptides are cleaved by lysosomal proteases following internalization of the resulting immunoconjugates. Conjugate 18b demonstrated antigen-specific in vitro tumor cell killing activity (IC(50)=0.2 microM) that was equipotent to DOX with a near doubling of drug molecules/MAb. Size exclusion chromatography showed 18b to be a noncovalent dimer that was formed immediately upon conjugation.

Antibodies, Monoclonal↗

PubMed2002

Synthesis of an immunoconjugate of camptothecin.

The first immunoconjugate of camptothecin has been synthesized wherein the drug is attached to the tumor-recognizing antibody BR96 via a Cathepsin B cleavable linker. Endocytosis of the immunoconjugate upon binding to the tumor cell followed by enzymatic cleavage of the linker inside the endosome ensures tumor-specific release of the drug. In this way, it is hoped that the dose-limiting side effects associated with camptothecin can be eliminated while the antitumor activity is preserved.

Camptothecin↗

PubMedDate not supplied

Surgical removal of an intramedullary spinal cord foreign body granuloma in a dog.

A 2-year-old, spayed female, mixed-breed dog was presented for evaluation of a progressive asymmetric tetraparesis and cranial nerve deficits with a 3-week duration. Computed tomography showed a contrast-enhancing lesion along the left side of the junction of the medulla and the cervical spinal cord. An exploratory surgery determined the presence of an intramedullary lesion of the first cervical spinal cord segment. The mass was removed through a dorsal midline myelotomy. Microscopic examination identified a foreign body granuloma that contained a dense, anisotropic outer wall, supporting the conclusion that the foreign body was of plant origin. The dog recovered to a more improved ambulatory status than prior to surgery.

Animals↗

PubMedDate not supplied

External hydrocephalus in two cats.

External hydrocephalus describes an accumulation of cerebrospinal fluid (CSF) between the cerebral hemispheres and the overlying arachnoid membrane, rather than within the lateral ventricles. Two young cats with encephalopathic signs were diagnosed with external hydrocephalus, one via magnetic resonance imaging and one via computed tomography. Both cats had abnormally large, broad heads, with no evidence of open fontanelles. A surgical shunt was placed in each cat to divert the accumulated CSF within the cranial cavity to the peritoneal space. Both cats improved dramatically soon after surgical shunting was performed, and they continue to do well clinically, approximately 42 months and 8 months postoperatively, respectively.

Animals↗